R. Dieden, D. Latinne, C. Baldari, Nicoletta Maton, A. Aubry, R. Verbeeck, M. Zurini, G. Lhoëst
Cyclosporin A (CsA) and IMM-125, a hydroxyethyl derivative of D-serine CsA, are cyclic undecapeptides of molecular weight 1201.8 and 1261.8, respectively. The main metabolites still possessing the undecapeptide structure were found to be compounds resulting from the biotransformation of amino acids 4, 9 and 1. Under the influence of the hepatic cytochrome P-450-dependent monooxygenase system, CsA and IMM-125 amino acid 1 are metabolized to a mono-hydroxylated compound (metabolite M-17) and to a dihydrodiol. A metabolite M18 was found to be the result of a non-enzymic intramolecular formation of a tetrahydrofuran derivative from metabolite M17. Since the existence of a CsA dihydrodiol was reported and since epoxides are considered as the dihydrodiol precursors, the aim of the present work was to prove that the same non-enzymic intramolecular formation of a tetrahydrofuran ring could occur by nucleophilic attack of the amino-acid 1 beta -hydroxy group at the epsilon -position of the freshly formed epoxide by reaction of IMM-125 with m-chloroperbenzoic acid and cyclosporin A with selenium oxide. The immunosuppressive activity of the compounds, as measured by the mixed lymphocyte reaction and by the luciferase activity of a Jurkat-T-cell line stably transfected with the NF-AT/luc reporter plasmid, was found negligible for IMM-125 compared to the parent drug as well as for the cyclosporin A derivative. Structures of the IMM-125 and CsA derivatives were elucidated by electrospray mass-spectrometry and NMR spectroscopy.
环孢素A (Cyclosporin A, CsA)和IMM-125是d -丝氨酸CsA的羟乙基衍生物，分子量分别为1201.8和1261.8。主要代谢产物仍具有非肽结构，是由氨基酸4、9和1的生物转化产生的化合物。在肝细胞色素p -450依赖的单加氧酶系统的影响下，CsA和IMM-125氨基酸1被代谢为单羟基化化合物(代谢物M-17)和二氢二醇。发现代谢物M18是代谢物M17的四氢呋喃衍生物的非酶分子内形成的结果。由于CsA二氢二醇的存在已被报道，并且环氧化合物被认为是二氢二醇的前体，因此本工作的目的是证明IMM-125与间氯过苯甲酸和环孢素a与氧化硒反应时，新形成的环氧化合物的epsilon位置上的氨基酸-1 -羟基的亲核攻击也可以发生同样的非酶分子内四氢呋喃环的形成。通过混合淋巴细胞反应和稳定转染NF-AT/luc报告质粒的jurkat - t细胞系的荧光素酶活性测量，发现与母体药物和环孢素a衍生物相比，IMM-125的免疫抑制活性可以忽略不计。通过电喷雾质谱和核磁共振谱对IMM-125和CsA衍生物的结构进行了表征。
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